Cost Considerations When Optimizing Sedation in the ICU

John W. Devlin, PharmD, FCCP, FCCM

Associate Professor

Northeastern University School of Pharmacy

Adjunct Associate Professor

Tufts University School of Medicine

Boston, Massachusetts

Faculty DisclosureIt is the policy of The France Foundation to ensure balance, independence, objectivity, and scientific rigor in all its sponsored educational activities. All faculty, activity planners, content reviewers, and staff participating in this activity will disclose to the participants any significant financial interest or other relationship with manufacturer(s) of any commercial product(s)/device(s) and/or provider(s) of commercial services included in this educational activity. The intent of this disclosure is not to prevent a person with a relevant financial or other relationship from participating in the activity, but rather to provide participants with information on which they can base their own judgments. The France Foundation have identified and resolved any and all conflicts of interest prior to the release of this activity.

Dr. Devlin has received grant/research support from Hospira. He has

served as a consultant for AstraZeneca and Hospira.

Curriculum Learning Objectives

• Manage adult patients who need sedation and analgesia while receiving ventilator support according to current standards and guidelines

• Use validated scales for sedation, pain, agitation and delirium in the management of these critically ill patients

• Assess recent clinical findings in sedation and analgesia management and incorporate them into the management of patients in the acute care and procedural sedation settings

Activity Learning Objectives

• Understand the sedation-related factors that may influence patient care costs in the ICU

• Discuss the influence of sedation protocolization and interruption on care costs

• Compare the cost-efficiency of available sedation regimens in the ICU

• Develop a cost-effective regimen for sedation in the ICU

ICU Sedation: The Balancing Act

Oversedation

• Prolonged mechanical ventilation• Increase length of stay• Increased risk of complications - Ventilator-associated pneumonia• Increased diagnostic testing• Inability to evaluate for delirium

Undersedation

• Patient recall• Device removal• Ineffectual mechanical ventilation• Initiation of neuromuscular blockade• Myocardial or cerebral ischemia• Decreased family satisfaction w/care

Patient Comfort and Ventilatory Optimization

GOAL

Jacobi J, et al. Crit Care Med. 2002;30:119-141.

Influence of Sedation Practices on Health Care Costs Outcomes and Costs of Undersedation

• Tachycardia ⇨ myocardial ischemia• Use of neuromuscular blockers

– Prolonged neuromuscular weakness common– Median $66,713 in additional costs (1995 costs)

• Short and long-term psychological effects• Cost of device removal

– 10 patients removed 42 devices (GI/vascular)– 74% were “significantly agitated” within 2 hr– Total $7606 or $181/event (1997 costs)– Annual cost at 42-bed ICU > $250,000

Dasta JF, et al. Crit Care Clin. 2009;25:571-583.Rudis MI, et al. Crit Care Med. 1996; 24:1749-1756.Fraser GL, et al. Pharmacotherapy. 2001;21:1-6.

.

Oversedation in the ICU Is Common

• N = 274 MICU patients

• 32% unarousable

• 21% no spontaneous motor activity

Weinert CR, et al. Crit Care Med. 2007;35:393-401.

• Little variation over 24 hours in LOC, motor activity, or drug dose given

• RNs thought only 2.6% of patients were “oversedated”

Payen J, et al. Anesthesiology. 2007;106:687-695.

• More days on mechanical ventilation = more of the costly negative sequelae associated with mechanical ventilation: – Ventilator-associated pneumonia:

Occurs in 10%-20% of patients receiving mechanical ventilation for > 48 hrs Mean ICU LOS of 6.1 additional days (95% CI, 5.32-6.87) Additional cost of evaluating and treating a patient with VAP = $10,019

– Venous thrombosis: Incremental cost per event = $3,000 (in 2000 $)

• Costs associated with increased use of head CT scan/neurology consult• Costs associated with increased frequency of sedation-related adverse events and drug withdrawal effects

– Propofol-related infusion syndrome– Lorazepam-related propylene glycol toxicity

• Costs associated with increased neurocognitive sequelae– PTSD– Delirium

Costs of Oversedation in the ICU

Safdar N, et al. Crit Care Med. 2005; 33:2184-2193.Dasta JF, et al. Crit Care Clin. 2009; 25:571-583.Devlin JW, et al. Crit Care Med. 2010 (in press).Gunther ML, et al. Crit Care Clin. 2007; 23:491-506.

Influence of Sedation Practices on Health Care Costs

• ICU costs account for more than 1/3 of total inpatient costs• Incremental cost of mechanical ventilation = $1522 per day

Dasta JF, et al. Crit Care Med. 2005;33:1266-1271.

• Use of a spontaneous awakening–spontaneous breathing trial protocol reduces duration of mechanical ventilation and length of ICU stay

Girard TD, et al. Lancet. 2008;371:126-134.

Influence of Sedation Practices on Health Care Costs

Outcome SBT SAT+SBT P-value

Ventilator-free days 12 15 0.02

Time-to-event, days

Successful extubation 7 5 0.05

ICU discharge 13 9 0.01

Hospital discharge 19 15 0.04

Pharmacist-Enforced Sedation Protocol• 156 MICU patients prescribed continuous sedation • Protocol encouraged 25% down-titration when patients

more sedated than goal• Before/after design evaluating impact of pharmacist

promoting protocol on at least a daily basis.

Marshall, J, et al. Crit Care Med. 2008;36 (2):427-433.

0

2

4

6

8

10

Pharmacist-Led Control

Med

ian

Day

s o

f M

ech

anic

al V

enti

lati

on

5.2

6.9

P < 0.00101

Influence of Sedation Practices on Health Care Costs: Delirium

• Choice of sedative influences incidence of delirium• Delirium is associated with increased health care costs

Milbrandt EB, et al. Crit Care Med. 2004;32:955-962.

$ 9,014

$ 14,730

Hospital CostICU Cost

$41,836

$27,106

$22,346

$13,332

Never Delirium (n = 41)

Ever Delirium (n = 183)

All P ≤ 0.002

$0

$10,000

$20,000

$30,000

$40,000

$50,000

Med

ian

Cos

t

Characteristics of the Ideal ICU Pharmacoeconomic Study

• Decision tree that is consistent with standard ICU care – Developed by multidisciplinary panel of experts – Includes all possible alternative therapies (eg, choice of

sedative) as well as the most important positive and negative clinical outcomes

• Use of rigorous RCT(s) to define efficacy• Cost estimates (ie, drug costs, patient charges etc)

should be collected prospectively• Costs related to drug dispensing, administration,

monitoring and adverse events should be included• Comprehensive sensitivity analysis

Hay JW, et al. Value Health. 2009 Oct 28. [epub ahead of print] Dasta JF, Kane-Gill SL. Crit Care Clin.

2009;25:571-583.

Cost-Effectiveness Analysis

• Compares cost and outcomes of two different interventions

• All costs are related to a single, common outcome – Duration of mechanical ventilation, mortality

• Helps answer the question: Is a new therapy with a higher acquisition cost worth it?

• A useful tool to help improve health care resource utilization at both the bedside and the institutional (eg, guidelines) level

Hay JW, et al. Value Health. 2009 Oct 28. [epub ahead of print]

Cost-Effectiveness Analysis Outcomes

• Intermediate effectiveness outcomes/surrogate endpoints – mm Hg blood pressure reduction– % serum cholesterol reduction– Duration at the targeted level of sedation

• Final effectiveness outcomes – Mortality, years of life gained, presence of disease– Length of mechanical ventilation or ICU stay– Preferred but not easily measured

Cost Minimization Analysis

• Compares two or more treatments demonstrated to have equal efficacy

• Cost is measured in dollars • A measure of efficacy (eg, duration of

mechanical ventilation) is not measured since it is assumed to be equivalent between 2 groups

• Helps the clinician(s) choose the least costly treatment

Hay JW, et al. Value Health. 2009 Oct 28. [epub ahead of print]

Drug Acquisition Cost(70 kg patient, per day)

• Lorazepam 3 mg/hr: $35• Midazolam 5 mg/hr $42• Propofol 30 mcg/kg/min: $150• Dexmedetomidine 0.5 mcg/kg/hr: $274

Tufts Medical Center 2010 Pricing

2

Anis A, et al. Anesthesiology. 2002;96:196-201.

Propofol vs Continuous Midazolam• Randomized, unblinded pharmacoeconomic study• Considered sedation drug costs and costs associated with ICU care (eg, MD

consult, RN care, testing, etc) but did not measure actual ICU LOS or charges associated with it

• Propofol resulted in faster extubation time• LOS in the ICU and total cost per patient did not differ

Extubation Time Sedative Drug Cost

Coefficient P-value Coefficient P-value

Constant 0.58 0.02 4.61 0.001

Treatment effect (TE) Propofol vs midazolam

-1.43 0.001 1.27 0.001

Sedation time (ST) 0.003 0.04 0.007 0.001

Interaction TE x ST Propofol vs midazolam

-0.005 0.02

Analysis of Covariance*

*Both extubation time and sedative drug cost were log-transformed

Midazolam vs Lorazepam vs Propofol

• Hypothetical cohort study• Compared the expected costs of short,

intermediate and long-term sedation with propofol, lorazepam and midazolam– Preparation, administration, adverse drug

reactions (ADRs), therapeutic failures

• Relied on estimates from already published studies

MacLaren R, et al. Pharmacotherapy. 2005;1319-1328.

Midazolam vs Lorazepam vs Propofol

MacLaren R, et al. Pharmacotherapy. 2005;1319-1328.

Total Cost ($) Probability of Being Least Costly (%)

Short Lorazepam 497 0

(13.5 hrs) Midazolam 294 14

Propofol 272 86

Intermediate Lorazepam 932 0

(14.3 hrs) Midazolam 587 97.5

Propofol 674 2.5

Long Lorazepam 1604 84

(119.8 hrs) Midazolam 1737 16

Propofol 2003 0

Scheduled Intermittent Lorazepam vs Propofol with Daily Interruption in MICU Patients

Carson SS, et al. Crit Care Med. 2006;34:1326-32.

Lorazepam (N = 64) Propofol (N = 68) P-value

Ventilator days (median)

8.4 (4.6 to 14.7) 5.8 (3.5 to 10.3) 0.04

ICU LOS 10.4 (6.7 to 16.8) 8.3 (5.2 to 15.2) 0.20

APACHE II 22.9 ± 7.7 20.7 ± 7.3 0.05

Daily sedation dose

11.5 (3.8 to 22.7) mg 24.4 ± 16.3 mcg/kg/min

-

Morphine dose (mg/day)

10.7 (5.4 to 25.8) 31.6 (16.2 to 71.6) 0.001

Use of haloperidol

12% 9% 0.80

Cox CE, et al. Crit Care Med. 2008;36:706-714.

Intermittent Lorazepam vs Propofol (DIS in both arms)

DIS= Daily Interruption of Sedation

• Use of propofol associated with lower total costs ($45,631 vs $52,009)

• Three more ventilator-free days with propofol• Propofol was less costly or more effective in 94% of the

1000 simulations

Cox C, et al. Crit Care Med. 2008;36:706-714.

Propofol Is More Cost-Effective Than Intermittent Lorazepam

Propofol is More Cost-Effective Than Intermittent Lorazepam

`

Cox CE, et al. Crit Care Med. 2008;36:706-714.

Propofol less expensive

Lorazepam moreeffective

2 0.5

HighLow

$9,488$1,825

$631

5%75%

$1,892

20% 0%c

0%20%

MidazolamLorazepam

Low

$11.37 $60.77

4,347 949

$7.82$0.81

423

Ratio of propofol to lorazepam MV days

Average duration of MV

Cost of ICU day

Hospital mortality

Cost of hospital ward day

Probability of propofol intolerance

Probability of lorazepam intolerance

Crossover group from propofol

Physician costs

Cost of propofol

Daily propofol dose, mg

Cost of lorazepam

Daily lorazepam dose, mg

-$35 -$30 -$25 -$20 -$15 -$10 -$5 $0 $5 $10 $15 $20 $25 $30 $35

Cost Difference Between Lorazepam and Propofol ($ Thousands)

High

Addition of Dexmedetomidine to Midazolam and/or Propofol in Cardiac Surgery Patients

Reduced Mean Total Treatment Charges

• 12-month retrospective administrative claims database analysis

• Comparison of patients receiving either midazolam plus propofol (M+P) or dexmedetomidine plus M+P (D+M+P)

• The D+M+P cohort showed significant reductions in per patient total charges

M+P D+M+P0

20

40

60

80

100

120$106K

$89K

Tre

atm

en

t C

ha

rge

s,

$T

ho

us

an

ds

P < 0.05

M+P, n = 9996D+M+P, n = 356

Dasta JF, et al. Pharmacotherapy. 2006;26:798-805.

P < 0.01

Mean Length of Stay

P = 0.1074

Mortality Rate

M+P, n = 7577D+M+P, n = 293

M+P D+M+P0

20

40

60

80

100

120

$97K

$80K

Ch

arg

es

, $

Th

ou

sa

nd

s

P < 0.05

Mean Total Charges

M+P D+M+P0

1

2

3

4

5

6

7

8

9

108.9

8.1

Me

an

Da

ys

M+P D+M+P0

0.5

1

1.5

2

2.5

3

2.5%

1.0%

Mo

rta

lity

Ra

te,

%

Dasta JF, et al. Pharmacotherapy. 2006;26:798-805.

Addition of Dexmedetomidine to Midazolam and/or Propofol in Cardiac Vessel Surgery Patients

MENDS: Dexmedetomidine Versus Lorazepam

• Dexmedetomidine resulted in more days alive without delirium or coma (P = 0.01) and a lower prevalence of coma (P < 0.001) than lorazepam

• Dexmedetomidine resulted in more time spent within sedation goals than lorazepam (P = 0.04)

• Differences in 28-day mortality and delirium-free days were not significant

Pandharipande PP, et al. JAMA. 2007;298:2644-2653.

Day

s

Lorazepam n = 51

Dexmedetomidine n = 52

02

46

81

01

2 P = 0.011

Delirium/Coma-Free Days

Delirium-Free Days

P = 0.086 P = 0.001

Coma-Free Days

MENDS Trial: Cost of Care

$ – Costs represented in thousands, US dollars (Median, IQR)

Pandharipande PP, et al. JAMA. 2007;298:2644-2653.

Outcome Lorazepam Dexmedetomidine P-value

Pharmacy 20.6 (10,42) 27.4 (16,46) 0.15

Respiratory 2.9 (2,6) 3.5 (2,7) 0.35

ICU cost 59.5 (36,83) 61.4 (37,108) 0.32

SEDCOM Trial:Efficacy Outcomes

Riker RR, et al. JAMA. 2009;301:489-499.

Outcome Midazolam (n = 122)

Dexmedetomidine (n = 244)

P-value

Time in target sedation range, % 75.1 77.3 0.18

Patients completing daily arousal test 103 (84.3%) 225 (92%) 0.09

Patients requiring sedation interruption 112 (91.8%) 222 (91%) 0.85

Duration of sedation, days 4.1 3.5 0.01

Time to extubation, days 5.6 3.7 0.01

ICU length of stay, days 7.6 5.9 0.24

Delirium prevalence 93 (76.6%) 132 (54%) 0.001

Delirium-free days 1.7 2.5 0.002

Patients receiving open-label midazolam 60 (49%) 153 (63%) 0.02

Midazolam dose, mg/kg 0.11 0.09 0.65

Patients receiving fentanyl 97 (79.5%) 180 (73.8%) 0.25

Fentanyl dose, µg/kg 9.6 6.4 0.27

Riker, RR, et al. JAMA. 2009;301:489-499.

Time to Extubation ICU Length of Stay

P = 0.01 P = 0.24

SEDCOM Trial

Baseline 1 2 3 4 5 60

20

40

60

80

100

Pat

ien

ts W

ith

Del

iriu

m, %

Midazolam

Dexmedetomidine

dexmedetomidine versus midazolam, P < 0.001

SEDCOM Trial: Prevalence of Delirium

Sample Size 118 229 109 206 92 175 77 134 57 92 42 60 44 34

Riker RR, et al. JAMA. 2009;301:489-499.

Treatment Day

A Cost Minimization Analysis of a Clinical Trial Dexmedetomidine vs Midazolam

• Assumed equal sedation efficacy – Cost minimization analysis

• Compared costs of care between groups and selected the therapy generating the lowest cost

• Economic analysis performed post-hoc and from the institutional perspective

• Costs were estimated from multiple databases and published literature

Dasta JF, et al. Crit Care Med. 2010;38:497-503.Riker RR, et al. JAMA. 2009;301:489-499.Dasta JF, et al. Crit Care Med. 2005;33:1266-1271.

• Components of total ICU costs– Cost of ICU stay

– Cost of mechanical ventilation

– Cost of adverse drug reactions probably or possibly related to study drug

– Acquisition cost of study drugs

• Median regression approach was used to compare two treatment regimens

Dasta JF, et al. Crit Care Med. 2010;38:497-503.

A Cost Minimization Analysis of a Clinical Trial Dexmedetomidine vs. Midazolam

Dasta JF, et al. Crit Care Med. 2010;38:497-503.

SEDCOM Cost of Care

• Median drug costs• Dex $1166• Midazolam $60

• Total ICU patient savings with Dex: $9679

• Reduced ICU stay • Reduced MV

A Cost Minimization Analysis of a Clinical TrialDexmedetomidine vs Midazolam

Dasta JF, et al. Crit Care Med. 2010;38:497-503.

Summary

• Choice of sedation practices have a substantial influence on the cost of care in the ICU

• Maintaining patients at the sedation goal through sedation protocolization (that may include daily sedation interruption) will avoid the costly sequelae of both under- and oversedation

• Both propofol and dexmedetomidine are more cost-beneficial than benzodiazepines

• Future studies need to evaluate the cost-effectiveness of propofol vs dexmedetomidine in non-cardiac surgery ICU patients